Lung cancer is the leading cause of cancer-related death worldwide. Currently, patients with metastatic lung cancers are treated with empirically chosen cytotoxic agents: Recently, the epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), gefitinib and erlotinib, have shown dramatic activity in 10-28% of patients with advanced non-small cell lung cancer (NSCLC). We and others have shown that responses to these agents are associated with mutations in the TK domain of EGFR. This development heralds an initial transition to individualized molecular therapeutics for NSCLC patients but also poses new challenges, as nearly all patients who demonstrate dramatic benefits when treated eventually suffer progression of disease. Molecular mechanisms underlying events that contribute to "acquired" drug resistance are poorly characterized. Understanding how NSCLC becomes "resistant" to EGFR TKIs will accelerate development of rational strategies for overcoming acquired resistance. This approach is supported by recent studies of another targeted agent, imatinib, in patients with BCR-ABL-dependent chronic myelogenous leukemia (CML). CML tumor cells from imatinib-treated patients who develop resistance to this agent contain mutations within the kinase domain of ABL or less frequently, amplification of the BCR-ABL genomic locus. These insights have led to new ways to surmount imatinib resistance in the clinic. To determine if analogous mechanisms apply to acquired EGFR TKI resistance, we propose correlative studies to accompany two clinical trials using erlotinib in NSCLC. Specific Aims include 1-To compare the sequence of the TK domain of EGFR in initially sensitive and subsequently "resistant" tumors derived from individual NSCLC patients treated with erlotinib, 2-To determine how newly "acquired" mutations affect biochemical properties of EGFR mutants, including sensitivity to erlotinib, and 3-To compare EGFR copy number in initially sensitive and subsequently "resistant" tumors derived from individual NSCLC patients treated with erlotinib.